Systemic lupus erythematosus (SLE) is a systemic inflammatory autoimmune disease that affects predominantly young, minority, pre-menopausal women. Up to 75% of patients with SLE experience some type of nervous system manifestations during their disease course (termed neuropsychiatric lupus or NPSLE). The most common manifestations include cognitive dysfunction, psychiatric disease and stroke, although the full range of NS involvement has not been well characterized. Two major areas of the candidate's research have been the study of 1) clinical and serologic predictors for the development of NPSLE, and 2) immune-mediated thrombosis related to antiphospholipid antibodies (aPL). The major thrust of this proposal will be to expand a strong clinical research program studying NPSLE in a cohort of predominantly Mexican-American SLE patients by 1) determining the frequency of and risk factors for accelerated atherosclerosis in this well-defined cohort and 2) evaluating the frequency and of microembolic signals (MES) by transcranial doppler (TCD) and the relationship between MES and cerebrovascular ischemia and cognitive dysfunction in 2 cohorts of SLE patients (UTHSCSA and Dusseldorf, Germany) with and without aPL. SLE patients are at increased risk for thrombotic events, including both myocardial infarction and stroke. Several NPSLE manifestations may have cerebral ischemia as a common underlying pathophysiologic mechanism, e.g. cognitive dysfunction and stroke. Potential causes of ischemia in SLE include vasospasm, microvascular disease, thrombosis with or without atherosclerosis, and rarely, vasculitis. The frequency of atherosclerosis in SLE, the importance of atherosclerosis in SLE-related stroke risk, or whether there are important genetic or racial influences are unknown. Traditional vascular risk factors, inflammatory, immunological, and treatment-related factors specific to SLE are all likely to be involved. With the support of the Mid-Career Investigator Award, the candidate will work with a multidisciplinary team of established investigators and fellows in the areas of stroke, vascular and brain imaging, immunogenetics, epidemiology, psychiatry and neuropsychology. This collaborative effort will provide very important information regarding prevalence and extent of sub-clinical vascular disease and associated risk factors in SLE. Much will be learned about the relative importance of genetic factors and autoantibodies on vascular disease risk in SLE that is likely to apply to other populations also at increased risk for cerebral ischemia and vascular dementia.